REVIEW ARTICLE Neurologia i Neurochirurgia Polska Polish Journal of Neurology and Neurosurgery 2020, Volume 54, no. 1, pages: 21–27 DOI: 10.5603/PJNNS.a2020.0008 Copyright © 2020 Polish Neurological Society ISSN 0028–3843 Monoclonal antibodies — a revolutionary therapy in multiple sclerosis Carmen Adella Sirbu1, 2, Magdalena Budisteanu1,3,4, Cristian Falup-Pecurariu5,6 1Titu Maiorescu University, Bucharest, Romania 2‘Dr. Carol Davila’ Central Military Emergency University Hospital, Clinic of Neurology, Bucharest, Romania 3‘Prof. Dr. Alex Obregia’ Clinical Hospital of Psychiatry, Psychiatry Research Laboratory, Bucharest, Romania 4‘Victor Babes’ National Institute of Pathology, Bucharest, Romania 5Faculty of Medicine, Transylvania University of Brașov, Brașov, Romania 6Department of Neurology, County Emergency Clinic Hospital, Brașov, Romania ABSTRACT Introduction. Multiple sclerosis (MS) has an increasing incidence and affects a young segment of the population, having a major impact on patients and consequently on society. The multifactorial aetiology and pathogenesis of this disease are incompletely known at present, but autoimmune aggression has a documented mechanism. State of the art. Since the 1990s, immunomodulatory drugs of high efficacy and a good safety profile have been launched. But the concept of NEDA (No Evidence of Disease Activity) remains the target to achieve. Thus, the new revolutionary class of monoclonal antibodies (moAbs) used in multiple medical fields, from this perspective represents a challenge even for multiple sclerosis, including the primary progressive form, for which there has been no treatment until recently. Clinical implications. In this article, we will review monoclonal antibodies’ use for MS, presenting their advantages and di- sadvantages, based on data accumulated since 2004 when the first monoclonal antibody was approved for active forms of the disease. Future directions. There is still a need for personalised medicines, with a specific target, which should have fewer adverse effects and drug interactions. Key words: multiple sclerosis, monoclonal antibodies, safety, natalizumab, alemtuzumab, ocrelizumab (Neurol Neurochir Pol 2020; 54 (1): 21–27) Introduction of drugs in use today to which biosimilars/biogenerics are being added. Multiple sclerosis (MS) is characterised by inflammation, focal demyelination at multiple locations and by a process of State of the art axonal degeneration in a person with genetic susceptibility to the disease. It affects young people, with more women than The first drugs developed to treat MS were from the in- men, a ratio that is growing from 1.4/1 to 2.3/1 [1]. terferon class, and the first Food and Drug Administration The rational use of MS therapy, following current guide- (FDA) approval was granted in 1993 for Interferon beta 1b lines, patient particularities, and clinical experience, is an (IFNB-1b) [2]. Three years later, another drug – glatiramer important task that involves great responsibilities from all team acetate – was released onto the market. These drugs, known as members (patient, physician, and government structures). The disease-modifying therapies (DMTs), have shown a good long- physician’s role is even more difficult, given the wide range term safety profile but suboptimal efficacy [3, 4]. A substantial Address for correspondence: Magdalena Budisteanu, Titu Maiorescu University, Bucharest, Romania, e-mail: [email protected] www.journals.viamedica.pl/neurologia_neurochirurgia_polska 21 Neurologia i Neurochirurgia Polska 2020, vol. 54, no. 1 percentage of the treated patients withdraw from treatment or therapeutic purposes, approved by the FDA in 1992 to prevent change it because there is no real benefit [5]. Another problem, the rejection of transplanted organs. Muromonab (the only that has for decades decreased patient adherence to treatment, moAb that does not have the common ‘-mab’ suffix imposed is its administration method – by injection [6]. since 2008 in their terminology) targets the CD3 antigen and Researchers continue to investigate developing drugs that comes only from mice, with a high degree of immunogenicity. can stop the evolution of the disease (NEDA – no evidence of Thus, antibodies against these proteins of murine origin appear disease activity), with low costs, good safety profile and con- with repeated exposure to the drug. Through the development venient administration, to increase patient adherence to treat- of biotechnologies, this disadvantage has been largely solved as ment. Interferons and copolymers are useful because second- moAb dedicated to MS treatment is over 90% humanised (na- generation drugs, although more effective, come with a lower talizumab, alemtuzumab, and ocrelizumab — currently used) safety profile and higher costs. The pathogenic mechanism of or 100% human (ofatumumab, opicinumab, and secukinumab the disease has been partially identified. The initiation of the – in different stages of research) [11]. autoimmune process is done as we know it in the periphery. For Studies have revealed that by starting treatment as early as MS pathogenicity, B cells play an important role, modulating possible and with more active drugs, conversion to progres- antigen-presenting cells and T cell production and influencing sive disease may be delayed. Brown et al. studied this aspect the innate immunity [7]. Some antigens can activate cells of the by analysing transition from a relapsing form to a progressive immune system in individuals with a genetic predisposition disease for three categories of patients: those not treated or under the influence of environmental factors. These activated treated late, those treated with first-line DMTs (GA or IFNB), immune cells synthesise cytokines (interleukins IL 6, 17, 23, and those treated with more active drugs such as fingolimod, interferon-gamma, and TNF alpha, among others) with the alemtuzumab, and natalizumab. The results were conclusive. inflammatory role as well as activate Th lymphocytes towards The 1,555 patients were followed up with for at least four years. other pro-inflammatory lymphocytes. These cytokines activate The conversion rate to the progressive form of MS was lower the adhesion molecules from the capillary wall (VCAM, VLA in those treated with first-generation DMTs (GA and INFs) 4, E selectin, ICAM), altering the blood-brain barrier (BBB) compared to those with a natural evolution of disease (12% permeability. Endothelial cells play an important role in in- vs. 27%, 5-year absolute risk). Patients initially treated with flammation. For example, EndoMT is a novel process where natalizumab, alemtuzumab, and fingolimod had a progressive endothelial cells return to mesenchymal cells and lose their conversion rate of 7% versus 12%, as did those treated with ability to maintain brain homeostasis [8]. Through this auto- GA or IFNB after an average follow up of 5.8 years. If the immune cascade, inflammation, demyelination, and axonal escalation of the therapy (from GA and IFNB to natalizumab, damage appear from the earliest stages of the disease [9, 10]. alemtuzumab, or fingolimod) was done in the first five years These mediators of inflammation have been identified in MS and not later, the risk was 8% versus 14% (5-year absolute lesions, although it was for a long time considered that only risk) [17]. Harding et al. demonstrated that the average time self-reactive CD4 cells had this role [10]. The involvement of of 5-year progression to disability is shorter in patients whose the humoral immune response, which is more documented treatment escalation is later than it is in those who are treated nowadays, has turned antibodies against B cells into new aggressively from the beginning (3.14 vs. 6.0, p = 0.05). therapeutic targets [11, 12]. The integrity of the BBB is essential Thus, in the real world, early and aggressive treatment for the passage of drugs to the nervous system. Because of its of patients brings benefits compared to delayed treatment or high molecular weight, smaller amounts of moAb pass into the treatment with first-generation DMTs. However, comparative brain. Only 15% of 51 anti-cancer systemic drugs pass over an studies are needed to help establish therapeutic strategies [18]. intact BBB. MoAbs can be labelled with radioactive isotopes like 89Zr‐antibody‐PET. In this regard, PET imaging is in use Clinical implications in several clinical studies as a potential imaging biomarker for drug BBB penetration [13, 14]. The first moAb released onto the market was natalizumab, MoAbs are antibodies from identical immune cells, which approved by the FDA in 2004, 12 years after the discovery of are obtained from a stem cell by cloning. They are in a con- target integrin, for recurrent highly active relapsing forms of tinuous process of development, as were interferons in the MS [19, 20]. Natalizumab has already been used for 15 years glorious 1970s when they were considered to be remedies for in the US and 13 years in Europe. It acts on VLA-4 integrin on many diseases [15]. leukocytes and myeloid cells and limits their passage through We can say that both classes belong to biopharmaceuticals the BBB into the nervous system [21]. It also decreases LT that determine, due to their immunogenicity, the appearance reactivation and LB proliferation [22]. The AFFIRM and of anti-drug antibodies (ADAs), with unpleasant effects for SENTINEL studies were sufficient to obtain approval for pharmacokinetics and therefore for efficacy [16], hence draw- use (Tab.